BACKGROUND: Osteoarthritis (OA) is a chronic progressive illness for which early diagnostic options and effective therapy are needed. We hypothesize that periarticular factors such as body fatness and muscle function are important indicators of knee OA, and also hypothesize that risk for OA development can be estimated from observable characteristics in gait mechanics, and blood or urine protein profiles years before the OA becomes radiographically evident. [unreadable] [unreadable] EPIDEMIOLOGIC STUDIES OF OSTEOARTHRITIS AND AGING[unreadable] We have integrated clinically relevant measures of joint, bone and muscle function to assess musculoskeletal aging into the Baltimore Longitudinal Study of Aging (BLSA). Integration of these state-of-the-art imaging and physiologic measures of muscle, bone, and joints we will be better able to delineate healthy aging, the transition into common age-associated diseases (i.e. osteoarthritis, osteoporosis), and study the complex interplay between the processes that profoundly influence mobility function in late life. We have also conducted a study to delineate the relationship between muscle, bone and fat and knee OA, and explore the possible role of various inflammatory, metabolic and hormonal factors as mediators of these relationship using stored serum specimens obtained from BLSA participants up to 10 years prior to their developing radiographic knee OA. Blood samples have been tested using microarray platforms to detect proteins relevant to regulation of inflammation, cell growth and activation and metabolism along with serum and urine assays of cartilage and bone metabolism. We identified 16 proteins associated with OA, and 10 proteins that were differentially expressed years prior to OA classification. Results have been reported in a plenary presentation at the Scientific Meetings of the American College of Rheumatology, and the meetings of the Osteoarthritis Research Society International and will be submitted for publication. [unreadable] [unreadable] We have also conducted secondary analysis of BLSA data to test the hypothesis that individuals with hand OA have a higher likelihood of increased arterial stiffness compared to individuals without OA, even after adjusting for age. We examined pulse wave velocity and pulse pressure as surrogates of arterial stiffness in a subset of BLSA participants free of known cardiovascular disease and medications. Although significant individual relationships between arterial stiffness and various measures of hand OA were observed, this relationship appears attributable to the confounding effects of age. A manuscript reporting these results has been published.[unreadable] [unreadable] CLINICAL STUDIES OF KNEE OSTEOARTHRITIS[unreadable] Participants are being recruited for a clinical study to determine whether muscle strength, mass and function important determinants of mobility function in adults with knee OA, and explore the extent to which these characteristics are associated with local inflammatory factors and circulating biomarkers. Adults 50 years and older with and without OA of the knee of comparable age, body weight and physical activity level are being sought. A manuscript reporting changes in motor unit physiology are associated with early OA of the knee has been published. [unreadable] [unreadable] In collaboration with members of the Johns Hopkins Arthritis Center, we conducted a study to determine whether the inflammatory markers associated with knee OA change as weight reduction achieved by lifestyle physical activity modification and tailored exercise program. Lifestyle modification results in accumulated physical activity and exertion throughout the day and over the course of weeks. Tailored exercise incorporates exercises that are feasible for each individual. We will examine relationships between cartilage and bone biomarkers, knee pain and change in weight. Results were reported at the Osteoarthritis Research Society International meetings in December, 2005 and will be submitted for publication.[unreadable] [unreadable] Finally, since knee OA risk is substantially increased following surgical removal of the knee meniscus, we will also be studying the inflammatory response and its contribution to muscle malfunction in patients who undergo arthroscopic removal of damaged meniscus. We have proposed a study determine whether trauma, induced in the form of arthroscopic surgery of the knee, creates a local autoimmune process that alters muscle activation patterns locally thereby changing gait mechanics as well as disrupting the balance between parasympathetic-sympathetic reflexes. This process will contribute to development and progression of knee osteoarthritis. This will be a natural history study of joint trauma with 2 control groups in a series of 6 evaluations over 1 year. This study also includes a pilot investigation to identify local chemokines that may be important to the pathogenesis of early OA. We will be recruiting 24 healthy adults with meniscal damage for which arthroscopy is clinically indicated and 8 adults who have already undergone meniscal resection to serve as positive controls will be recruited from MedStar-associated orthopedic surgical practices. Controls will be matched to cases on the basis of age group, sex and body mass index (BMI). EMG and cytokine data obtained from healthy, age and sex matched BLSA participants will serve as historic controls (no additional data will be collected from BLSA participants who are not enrolled in this study). IRB approval has been obtained for this study.[unreadable] [unreadable] RESEARCH USING ANIMAL MODELS OF ARTHRITIS AND PHYSICAL INACTIVITY [unreadable] In close collaboration with the NMR unit of the Laboratory of Clinical Investigation, we previously conducted experiments to 1) delineate the functional and morphologic characteristics of skeletal muscle that are associated with arthritis, 2) determine whether arthritis-associated skeletal muscle properties is distinct from that induced by physical inactivity, and 3) explore the associations between muscle function, local and circulating inflammatory mediators. As we previously reported, collagen-induced arthritis and atrophy induced by hind-limb unloading both altered quadriceps muscle bioenergetics and contractile force, and also exerted measurable effects on bone quality that are assessed by micro-CT. Although these findings were accompanied by changes in skeletal muscle cytokine concentration, they correlated poorly with concentrations of circulating inflammatory mediators. In a subsequent study of similar design, we studied the effects of systemic erythropoietin on skeletal muscle bioenergetics and bone quality. A in-vitro bioreactor system has been developed that will allow us map the effects of other agents on skeletal muscle bioenergetics, thereby screening them for potential therapeutic value prior to animal testing. [unreadable] [unreadable] SUMMARY: A coordinated approach has been developed that spans epidemiologic, clinical and basic science that will explore mechanisms of osteoarthritis development and skeletal muscle malfunction in the context of aging and arthritis, and constitute a foundation upon which new therapeutic interventions strategies can be developed.